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Biomedical Integration of Metal–Organic Frameworks

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Trends in Chemistry

Review

Biomedical Integration of
Metal–Organic Frameworks
Sayan Banerjee,1,2 Christina T. Lollar,1,2 Zhifeng Xiao,1,2 Yu Fang,1 and Hong-Cai Zhou 1,
*

Metal–organic frameworks (MOFs) have recently been demonstrated to be Highlights

excellent platforms for biomedical applications. On account of their porous Metal–organic frameworks (MOFs) pos-
nature and modular structure, MOFs have served as bioactive-compound sess the rare and seemingly contradic-
tory advantages of complex, modular
carriers, cell-imaging materials, and therapeutic agents. MOF cavities allow
structures with exceptional structural
the encapsulation of a variety of guest molecules, facilitating controllable drug control and tunability necessary for
release and optical imaging. The metal components of MOFs make them suitable usage in intricate biological systems.
for magnetic resonance imaging (MRI) and computed tomography (CT).
In composite with other materials, MOFs
Additionally, MOF-embedded therapeutic agents have demonstrated promise can offer a protective layer for controlled,
in photodynamic and photothermal therapies. In this review, we describe several site-selective degradation and subse-
advanced examples that utilize MOFs in these cutting-edge applications. quent cargo release.
Investigation of the relationship between their structure and designated applica-
MOFs themselves have been impreg-
tion will enable future, informed exploration of MOFs for biomedical applications. nated with payloads such as enzymes,
DNA, proteins, therapeutics, photosensi-
tizers, and contrast agents for applica-
tions including enhanced or tandem
Biomedical Uses for MOFs catalysis, gene therapy, protein replace-
MOFs are porous materials well-established in the fields of gas storage, separation, and catalysis ment therapy, drug delivery, photody-
with infancy in biological applications [1,2]. MOFs comprise metal nodes and organic ligands namic therapy, photothermal therapy,
joined through coordination bonds. Due to the variability in metal-node and ligand geometries and imaging.

as well as extensive tunability through post-synthetic modification, MOF topologies and porosities The framework structures themselves
can be designed and tailored for specific biomedical demands. In addition, the order and crystal- can also be constructed with contrast
linity that MOFs possess facilitate their characterization by X-ray techniques not possible with agents or site-specific targeting groups.
amorphous materials. Although far less studied and validated than polymers, micelles,
dendrimers, or nanoparticles in biological applications, MOFs benefit from the groundwork laid
by other materials and may integrate lessons regarding particle size, toxicity, and site-specific
targeting strategies from other materials.

While MOF systems offer unique possibilities such as designable synergism and multifunction
materials (consider paramagnetic metal-ion clusters as MRI contrast agents in combination
with drug-loaded pores), they also produce unique challenges. For instance, since many MOFs
utilize toxic-metal building blocks, their tolerability in vivo is hindered and dependent on the com-
position and decomposition rate of the framework. To minimize risks of toxicity, intuition suggests
the use of MOFs with degradation products that are already endogenously present (e.g., amino
acids, biometals), although it is unclear whether MOFs formed from these subunits will be suitably
stable or porous, or possess sought-after properties. Methodical studies and summarizing per-
spectives are intermittently emerging to address the issue of toxicity, with the least toxic materials 1
Department of Chemistry, Texas A&M
appearing to be zeolite-like and iron-based MOFs, although studies tackling the considerable University, College Station, TX 77843,
USA
breadth of topologies, metal units, and organic components of MOFs are certainly far from real- 2
Equal contribution
ized [3–6]. Biodistribution and barrier permeability are incredibly size dependent and although
MOF particle sizes may be tuned, the reproducibility of a consistently narrow size range of
many MOFs is often relatively unreliable. For this reason, improved methodology in MOF nanopar- *Correspondence:
ticle synthesis is required if MOFs are to experience practical pharmaceutical usage. zhou@chem.tamu.edu (H.-C. Zhou).

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© 2020 Published by Elsevier Inc.
Trends in Chemistry

Recent significant advances of MOFs in biomedical applications may be divided into three Glossary
categories: (i) cargo encapsulation, protection, and delivery; (ii) biomedical imaging; and 1
O2: reactive excited state of oxygen
(iii) therapeutic agents. A brief survey of these examples is provided in Table 1 with the known to damage biological material,
MOF name, ligand, metal, biological integration method, and application highlighted. We cancerous cells included, if sufficiently
concentrated.
encourage the interested reader to explore preceding and more specialized reviews
Fluorophore: any species, usually a
concerning ‘bio-MOFs’, although it is our hope that this review will serve as an introduction dye, that emits light of a lower energy/
to a timely subfield of MOF applicability prime for growth in the coming years (Figure 1), higher wavelength than the excitation
to update more experienced readers on select progress made in the last 5 years, and to light source.
Glucose oxidase: dimeric enzyme
stimulate further MOF research in biomedical applications [7–10]. responsible for catalyzing the oxidation
of glucose.
Hosts with Biological Applicability Heat shock protein 70 small
Biologically relevant guest uptake, protection, and release are burgeoning domains of MOF appli- interfering RNA (Hsp70 siRNA): small
segment of RNA that interferes with the
cability by virtue of their extraordinary surface areas and porosities, chemically tunable interiors, translation of Hsp70 proteins, essential
and adjustable stability and toxicity. In these cases, the MOFs themselves are not the biologically for normal protein folding.
active species but are instead vehicles for such species. Figure 2 presents information regarding Horseradish peroxidase (HRP):
heme-containing enzyme capable of
the chemical effects exploited to produce these applications as well as uptake, activity compar-
indirectly oxidizing several organic
isons, and release of MOF cargo from the papers discussed later. substrates. HRP is often used in
conjunction with oxidation-activated
Guest Release dyes.
Fascinated by what advantages MOFs could afford sustained or site-selective delivery, guest Microperoxidase-8: peptide segment
of cytochrome c containing a heme
release has been the most popular of the three abovementioned MOF-as-host applications. In moiety with the ability to oxidize
particular, smart MOFs, a subcategory of MOFs responsive to external stimuli such as light, peroxides.
pH, temperature, pressure, or external fields, have been exploited to spatiotemporally regulate Multivariate MOFs: MOFs possessing
guest release [11]. multiple metal or organic structural
building units or pore geometries, while
maintaining the order seen in standard
Dong and coworkers published an elegant report on diffusion-driven guest release profiles of ibu- MOFs; often abbreviated as
profen, rhodamine B, and doxorubicin (DOX) in multivariate MOF (see Glossary) hosts [12]. MTV-MOFs.
P-Glycoprotein: transmembrane
Diffusion-driven drug release is promising due to its potential for prolonged, gradual release rather
ATP-driven efflux pump amenable to a
than burst release and its associated side-effects. While MIL-101(Fe) typically comprises iron-oxo wide variety of substrates. This protein is
clusters and benzene dicarboxylate linkers, their group used normal benzene dicarboxylic acid as excessively expressed in multidrug-
well as the derivatives 2-aminobenzene-1,4-dicarboxylic acid and 1,4-naphthalenedicarboxylic resistant cancer cell lines, capable of
reducing intracellular drug
acid in varying ratios to produce a continuum of MOFs. Disparities in the release rates of each
concentrations.
type of cargo were observed depending on the linker percentages in the MOF. Using a host– Photodynamic therapy (PDT):
guest interaction parameter, a guest–guest interaction parameter, and a time variable, they therapy that employs light to activate
employed a mathematical model to predict the fraction of guest released. Although these studies photosensitizing agents, to then kill cells
often through the generation of singlet
were not performed in vivo, they are essential to pave the way for more clearly programmable oxygen.
MOF systems and to address the Goldilocks issue of host–guest interactions: when host– Photothermal therapy (PTT): therapy
guest interactions are too strong the guest may struggle to be released, while interactions that that employs light to activate a photo-
absorbing agent, to then kill cells often
are too weak may result in the guest being unable to efficiently load into the material.
through the generation of local heat.
Secondary building unit (SBU): refers
In contrast to diffusion-based release methods, decomposition-dependent release is another to a subunit of a MOF’s structure, most
popular approach that requires either dissociation of the framework or the dissociation of some commonly the metal cluster.
Upconversion: process by which the
surface, pore-blocking layer to release cargo. In general, a MOF’s stability is limited by the
absorption of two lower-energy photons
strength of the coordination bond between the linker and the metal cluster. Exposure to species is translated into the emission of light at a
that impede this bonding, such as acids that may protonate the linkers or hydroxide-producing higher energy/lower wavelength.
species that occupy sites on the metal cluster, can result in weakening and eventual decompo- π–π interaction: attractive force that
optimizes orbital overlap between pi
sition of the framework. Various factors ought to be considered to predict and understand systems.
MOF stability, including the ligand pKa, the oxidation state of the metal, the coordination number
and coordination-sphere size of the metal cluster, the Pearson hard/soft acid/base match be-
tween the binding species, and the hydrophobicity/hydrophilicity of the MOF pore environment.

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Table 1. Highlighted MOFs Used in Biological Applications Over the Past 5 Years
MOF Metal Ligand Biological integration Application Highest Refs
method model used
DBP-UiO Hf 5,15-Di(p-benzoato) porphyrin Singlet oxygen PDT In vivo [50]
generation
DBC-UiO Hf 5,15-Di(p-benzoato)chlorin Singlet oxygen PDT Cell [51]
generation
PCN-224 Zr Tetrakis(4-carboxyphenyl) porphyrin FA modification Targeted cancer treatment through Cell [52]
PDT
PCN-888 Al 4,4′,4′′-s-Heptazine-2,4,6-triyl- Encapsulation Dual-enzyme protection for tandem Solution [35]
tribenzoic acid catalysis
UiO-66 Zr 2-Amino-1,4-benzenedicarboxylic acid Encapsulation Thermo-, pH-, and Ca2+-triggered Cell [24]
cargo release
ZIF-90 Zn Imidazole-2-carboxyaldehyde Encapsulation Extremely low-frequency alternating Solution [28]
magnetic field-induced cargo release
ZJU-800 Zr (2E,2E′)-3,3′-(2-Fluoro-1,4-phenylene) Encapsulation Pressure-controlled cargo release Cell [27]
diacrylic acid
MIL-100 Fe Trimesic acid Targeting group Guided cancer therapy In vivo [48]
attached in the MOF
MIL-53-NH2 Fe 2-Amino-terephthalic acid Encapsulation and MRI targeting agent Cell [43]
surface modification
UiO-66 Zr Terephthalic acid Attaching BODIPY CT scan agent In vivo [44]
89
UiO-66 Zr Terephthalic acid Radioactive SBU PET scanning In vivo [46]
Hf-BPY-Ir,Ru Hf Ir[bpy(ppy)2]+ and [Ru(bpy)3]2+-derived Energy transfer PDT in low radiation dose In vivo [56]
tricarboxylate through Hf to Ir to
generate ROS
PCN-333 Al 4,4′,4′′-s-Triazine-2,4,6-triyl-tribenzoic Encapsulation Enzyme protection for prodrug In vivo [32]
acid activation
ZIF-8 Zn Imidazole Coating onto pH-triggered degradation for cargo Cell [16]
cargo-loaded release
mesoporous silica
IRMOF-74-II-V Ni 2,5-Dioxidoterephthalic acid and Encapsulation Protection and delivery of ssDNA Cell [30]
derivatives
PCN-TTA-UC Zr 4,4′-(Anthracene-9,10-diyl)dibenzoic Triplet-triplet annihilation Imaging In vivo [49]
acid upconversion
Hf6-DBA, Hf 2,5-Di(p-benzoato)aniline Harvesting X-rays for X-ray PDT combined with In vivo [58]
Hf12-DBA ROS generation immunotherapy
MIL-127 (Fe) Fe 3,3′,5,5′-Azobenzene tetracarboxylic Encapsulation Gastrointestinal toxin uptake Ex vivo [36]
acid
ZIF-8 Zn Imidazole Encapsulation Protein preservation and Cell [22]
pH-triggered release
MIL-101 (Cr) Cr Terephthalic acid Encapsulation Enzyme protection for the Solution [34]
degradation of organic dyes
Zr-FeP Zr Tetrakis(4-carboxyphenyl) porphyrin Hsp70 siRNA loaded Combined therapy of PDT and PTT In vivo [61]
Hf-DBB-Ru Hf Bis(2,2′-bipyridine)(5,5′-di(4-benzoato)- Harvesting X-rays for X-ray PDT targeting at mitochondria Cell [59]
2,2′-bipyridine)ruthenium (II) chloride ROS generation
H-MOF(Zr) Zr 2-Aminoterephthalic acid Encapsulation Enzyme protection for wastewater Solution [33]
pollutant degradation
MIL-100 Fe Trimesic acid Encapsulation Cargo delivery Cell [31]
HKUST-1 Cu Trimesic acid Encapsulation Cargo delivery Cell [31]
UiO-66 Zr Terephthalic acid Encapsulation Cargo delivery Cell [31]
(continued on next page)

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Table 1. (continued)
MOF Metal Ligand Biological integration Application Highest Refs
method model used
UiO-67 Zr Biphenyl dicarboxylic acid Encapsulation Cargo delivery Cell [31]
NU-1000 Zr Tetraethyl 4,4′,4″,4″′- Encapsulation Uptake of protein-bound uremic Solution [37]
(pyrene-1,3,6,8-tetrayl)tetrabenzoate toxins
NMOF Zn Bola-amphiphilicoligo-(p-phenylene Encapsulation Solvent-responsive morphology Cell [29]
ethynylene) dicarboxylic acid changes and subsequent cargo
release
PCN-224 Zr Tetrakis(4-carboxyphenyl) porphyrin Encapsulation and Enhanced PDT In vivo [65]
MnO2 coating
ZIF-8 Zn Imidazole Encapsulation NIR-light-responsive cargo release Cell [25]
ZIF-8 Zn Imidazole Encapsulation DNAzyme preservation and In vivo [7]
pH-triggered release
Cu(Gallate) Cu Gallic acid Encapsulation Simultaneous drug and PDT In vivo [26]
(H2O) photosensitizer delivery
ZIF-8 Zn Imidazole Coating onto cargo- pH-responsive degradation for Solution [17]
loaded helical nanobot cargo release
MIL-100 Fe Trimesic acid Coating onto H2O2 and GSH dual-responsive Cell [21]
cargo-loaded PMMA cargo release

Trends in Chemistry

Figure 1. General Trends and Milestones in the Use of Metal–Organic Frameworks (MOFs) in Biomedical
Applications. (A) Yearly growth of publications regarding the biomedical application of MOFs. The data are retrieved from the
Web of Science search engine and include data until October 2019. (B) Major milestones in the biomedical application of MOFs.

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Figure 2. An Overview with Examples of the Mechanisms by which Metal–Organic Frameworks (MOFs) Are Used for Biologically Relevant Cargo.
(A) The three main modes by which MOFs are used as hosts for biologically relevant cargo: guest uptake, guest protection, and guest release. Mechanisms by which
these interactions are commonly accomplished are listed in the respective yellow boxes. (B) Uptake percentages for references discussed in the main text (i.e., [36,37]).
(C) Performance of free and MOF-incorporated enzymes compared [34,35]. (D) Cargo release profiles for references discussed in the main text (i.e., [12,17,21,24,31]).
Adapted, with permission, from [12,17,21,24,31,34–37].

A more in-depth discussion on MOF stability is available in various insightful reviews and book
chapters [13–15].

ZIF-8 is a framework comprising Zn-oxide clusters and imidazolate linkers. Although this MOF is
known to deteriorate under acidic conditions, this shortcoming can be exploited advantageously
for drug delivery applications since the decomposition products of ZIF-8 are considered biologi-
cally innocuous. Recently, judiciously designed composite materials have been constructed,
intelligently uniting the advantages of each component. For instance, Wang and coworkers

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constructed a microporous ZIF-8/mesoporous silica (MSN) hybrid nanocarrier cohered by

polydopamine (PDA) [16]. In this vehicle, steady decomposition of the ZIF-8 shell in the acidic
conditions of cancerous cell cytoplasts first releases curcumin to inhibit P-glycoproteins.
Following this, the now unblocked mesoporous cavities release their anticancer drug payload,
DOX. In another promising hybrid-material-based avenue, ZIF-8 loaded with rhodamine B as a
proof-of-concept cargo was coated onto a magnetically controllable helical nanobot [17]. The
3D-printed, tractable microstructure was magnetically guided while the pH-induced decomposi-
tion of ZIF-8 released the model cargo. This decomposition approach to cargo delivery may feel
familiar to those acquainted with drug delivery studies using other matrices, including polymers
and silica nanoparticles [18–20]. This methodology is widely applicable to MOF systems unstable
in biologically relevant microenvironments, such as reducing, glutathione (GSH)-concentrated or
acidic, oxidizing H2O2-rich locales.

In contrast to the preceding systems, Miao and coworkers focused on minimizing premature
drug release and related side-effects with a dual-responsive system [21]. This system features
a PDA outer layer to provide biocompatibility until the MIL-100 MOF interlayer encounters the
H2O2-rich extracellular environment of a cancerous cell, at which point the MOF decomposes
revealing the final DOX-incorporated polymethylacrylic acid layer, which is then disintegrated
under reducing endosomal conditions. This concept was first studied in vitro in buffered
solution to simplify the quantification and comparison of drug release profiles under different
conditions. They began with exposure of the drug-loaded system in buffered solutions to
H2O2 at normal physiological concentrations (0.5 μM) as well as pathological concentrations
(50 μM) for 48 h followed by treatment with GSH (reducing) at 10 μM (similar to the concentra-
tion in extracellular trafficking pathways) and 10 mM for 48 h, at pH = 7.4 and pH = 5.0 at either
room temperature or 37°C, where the decreased pH and increased temperature resulted in
enhanced release of DOX. This examination was followed by cellular studies on PC-3 cells,
tumor cells that express higher concentrations of H2O2, using confocal laser scanning micros-
copy to confirm intracellular release of the DOX molecules (particularly into the cell nuclei)
without supplementary addition of H2O2 or GSH. Although complicated, each component of
this matrix serves an elegantly designed purpose. The authors did not report such experi-
ments, but the selection of other internal MOFs or polymer materials with varying degrees of
stability or further customization through surface functionalization with biocompatible modules
could conceivable lead to high cell viability or further protection of the interior material,
prolonging the time before decomposition and release or enabling extended release of drug
cargo that may result in less severe medication-related side-effects, discourage premature
release, and reduce the need for re-administration.

Finally, it is also being realized that larger cargo, such as proteins for protein replacement therapy
[22] and DNAzymes for gene therapy [23], can be incorporated into stimulus-responsive release
systems. Rather than assuming the decomposition of the host framework, necessitating nontoxic
structural building units, Tan and coworkers have capitalized on the higher durability of
Zr-carboxylate frameworks, explicitly UiO-66, to construct a drug delivery vehicle that relies on
pH, temperature, or Ca2+ stimuli to dissociate CP5 rings blocking the release of internal guest
molecules [24]. As methods of mesopore generation advance, it is expected that the application
of MOFs to larger-scale cargo will advance in tandem.

Although diffusion-, pH-, and dissociation-based release mechanisms have seen the most use,
MOF-drug vehicles are also capable of light- [25,26], pressure- [27], magnetic field- [28], environ-
mental hydrophobicity/hydrophilicity- [29], and complementary DNA-induced [30] drug release
mechanisms. Analogously, Silvestre-Albero’s group endeavored to apply more MOF variety in

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drug delivery applications and has helped to lay the groundwork with a methodical analysis of the
loading, release, and cytotoxicity of four prevalent MOFs for intraocular therapeutics [31].

Guest Protection
Enzymes require very specific environments to preserve their folded structures and functionality,
rendering them vulnerable to minuscule variations in pH, temperature, or salinity. Their fragility
situates them as excellent candidates for another branch of MOF applicability: guest protection.
In contrast to guest delivery, the purpose of the MOF host is to provide a barrier between a fragile
payload and denaturing conditions to retain activity without cargo liberation. As of late, MOFs
loaded with enzymes have been employed for diverse applications such as the activation of
anticancer prodrugs [32] and degradation of toxic species in contaminated wastewater [33].

Recently, MIL-101(Cr) was loaded with microperoxidase-8, resulting not only in preservation of
the enzyme structure but also in enhancement of the oxidation rate of negatively charged methyl
orange over positively charged methylene blue [34]. Zhou’s group has pursued the immobilization
of two different enzymes, horseradish peroxidase (HRP) and glucose oxidase, in a hierarchi-
cally porous MOF, PCN-888, to yield a tandem nanoreactor [35]. Stepwise enzyme insertion
preferentially situates the larger enzyme in the larger pore and the smaller enzyme in the
medium-sized pore, granting the smallest pore space available for the diffusion of substrates
into and out of the MOF.

Guest Uptake
Finally, MOFs can internalize toxic species in biological environments, thereby mitigating damage
to surrounding cells. In one example, Rojas and coworkers found MIL-127(Fe) to be exceptional
at reducing intestinal salicylate absorption by a factor of 40, after which it is safely fecally excreted,
rendering it promising as an overdose treatment [36]. Additionally, nine Zr-based MOFs with dif-
fering linker size, linker geometry, metal-node connectivity, and overall topology were assessed
with regard to their efficiency in uremic toxin removal [37]. It was found that NU-1000 is an efficient
absorbent, almost entirely extracting p-cresyl sulfate from human serum albumin. This efficiency
was attributed to π–π interactions between the toxins and the pyrene-based ligands facilitated
by careful arrangement with hydrophobic adsorption sites and nearby hydrogen-bonding
capacities.

MOFs in Biomedical Imaging

Developments in biomedical imaging technologies assist in the diagnosis and detection of various
diseases. In the past decade, MOFs have been widely used to produce detectable signals or
enhance the contrast from targeted tissue, usually through modification of the MOFs’ metal
nodes (Figure 3). MRI, CT, and positron emission tomography (PET) are some of the most widely
used MOF-incorporated imaging techniques. Alternatively, the incorporation of fluorophores in
MOFs has also enabled optical imaging using upconversion in cells.

MRI
MRI employs radio-wave-frequency radiation under the influence of an external, gradient mag-
netic field to detect relaxation signals from the copious amounts of hydrogen atoms present in
biological systems. These signals provide precise anatomical-structure maps and help to detect
diseases and other anomalies. Gadolinium-based small molecules are the most commonly used
contrast agents; thus, Gd-based MOFs arose as logical MRI contrast agent candidates. Lin
and coworkers reported several experiments with Gd-containing nanoMOFs [38]. These Gd-
containing nanoMOFs possessed relaxation values about an order of magnitude higher than
the widely clinically used contrast agent Omniscan [39]. In another approach, encapsulating

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Figure 3. Metal–Organic Frameworks (MOFs) in Biomedical Imaging. (A) Highlighted elements (yellow, transition metals; purple, lanthanides) typically used as
metal clusters in MOFs applicable for bioimaging. (B) In vivo optical imaging of lymph nodes in mice using a triplet-triplet annihilation upconversion (TTA-UC) Zr MOF
platform (λex = 532 nm at 5 mW cm–2); 100 μl of TTA-UC MOF (2 mg ml–1) was injected in the footpad of mice. The images were taken at 5 min and 1 h after the
injection. (C) Hf-MnO2 nanoMOF composite used for magnetic resonance imaging (MRI). T1-weighted in vivo MR images of the nanoMOF are shown in transverse and
longitudinal sections of the mice. T1-weighted MR signals in the tumor and kidney are shown to prove the possible renal clearance of the nanoMOF. The relaxivity (r1)
values of the nanoMOF are shown under different pHs and different concentrations. (D) Radioactive 89Zr-based UiO MOF was used for in vivo PET imaging. Tumor is
shown in circle. (E) In vivo CT images of the ventral sides of rat after injection of UiO nanoMOFs at a dose of 0.1 mg g−1 body weight. Adapted, with permission, from
[44,46,49,66].

superparamagnetic nanoparticles into MOFs may produce effective contrast agents [40]. To
avoid toxicity concerns with Gd, some researchers have switched their attention to other
metal-based MOFs. Yang and coworkers developed Mn+2-based MOFs with near-IR dyes as
organic linkers, which were shown to act as MRI contrast agents [41]. Chowdhuri and coworkers
developed MOFs with internalized Fe3O4 nanoparticles [42]. Other Fe-based MOFs, such as
Fe-MIL-53 carrying chemotherapeutics or oligonucleotides, have been tested as MRI contrast
agents [43].

X-Ray CT Imaging
X-ray CT imaging, commonly referred to as CT scanning, provides a direct visualization of the
internal structures of a scanned object based on X-ray attenuation. X-rays are directed at an
object at different orientations and a series of tomographic cross-sectional images are obtained
to create a full 3D picture. Generally, high-atomic-number elements such as iodine, barium,
and bismuth are used as CT agents to contrast between tissues, and use of MOFs is advanta-
geous as higher-atomic-number elements can be easily incorporated into MOFs. For example,
Zhang and coworkers developed BODIPY-containing UiO-based frameworks named UiO-PDT.
In vivo CT imaging indicates preferential accumulation of MOF nanoparticles in tumor sites, pro-
viding enhanced contrast [44]. Sheng and coworkers reported a gold-nanoparticle-incorporated
MIL-88 MOF as a multifunctional diagnostic agent to give high-quality CT scans [45].

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PET
PET relies on the accumulation of positron-emitting radionucleotides at target organs, which emit
detectable gamma-ray photons on decay. Capture data from detector panels can then be com-
piled to generate a 3D image. Compared with other imaging techniques, PET imaging has better
detection sensitivity in the picomolar range. MOFs with positron imaging radioisotopes are suit-
able choices for this technique. Hong and coworkers developed intrinsically radioactive UiO-66
with 89Zr secondary building units (SBUs). These MOFs were further functionalized with
pyrene-derived polyethylene glycol (Py-PGA-PEG) and long peptide ligands [46]. These function-
alized nanoMOFs demonstrated strong radiochemical and material stability in various biological
media and acted as in vivo tumor-selective PET-imaging agents. Given that the half-life of 89Zr
is much higher (78 h) than that of the traditionally used 19F (2 h), these Zr-based PET agents
possess the potential for relatively long-term use.

Optical Imaging
Optical imaging is a minimally invasive technique whereby light illumination is used to visualize
tissue. However, this method suffers from the drawback of lower penetration depth. MOFs can
play a role in upconverting wavelengths in affected tissues. Li and coworkers developed core-
shell nanocomposite MOFs for luminescent imaging [47]. Cai and coworkers developed
hyaluronic acid-coated MIL-100 MOFs loaded with dyes for imaging-guided cancer therapy
[48]. Park and coworkers used a triplet-triplet annihilation upconversion system (TTA-UC) to
harvest low-energy photons in bioimaging. In their work, an anthracene-based Zr-MOF compris-
ing a porphyrinic photosensitizer was used. Due to the close proximity of the aligned chromo-
phores, this system does an excellent job in increasing TTA-UC, particularly in aqueous media,
demonstrative of an ideal in vivo imaging system [49].

MOFs as Therapeutic Reagents

Following developments in synthetic methodology for MOFs, the formation of MOFs with specific
functionality can be achieved through rational design of the organic linkers, metal clusters, and
topology. MOFs can be utilized as superior platforms for therapeutic applications, whereby the
therapeutic efficacy can be tuned and improved by judicious modifications to the structure.
More importantly, the porosity of MOFs facilitates interaction between external species and active
sites in the MOF structure and allows the encapsulation of therapeutic reagents to realize com-
bined therapeutics.

Photodynamic Therapy (PDT)

The most common therapeutic application of MOFs in the literature is to utilize MOFs as photo-
sensitizers in PDT. PDT is a kind of noninvasive cancer treatment developed in recent decades.
In this therapy, reactive oxygen species (ROS) are generated in the tumor cells by the excited
photosensitizer under irradiation by light and then the ROS can cause tumor cell apoptosis and
necrosis (Figure 4A). Compared with conventional therapies (chemotherapy, radiotherapy, and
surgical tumor removal), PDT has minimal systemic side effects. However, the photosensitizers
used are usually π-conjugated organic molecules with poor solubility and a tendency to aggre-
gate in cellular environments. Moreover, PDT cannot address metastasis of the tumor cells.
MOFs can be integrated with photosensitizers on the organic linkers to then carry into the
tumor cells. Figure 4B shows the common linkers integrated in MOFs for PDT. In 2014, Lin and
coworkers [50] first applied MOF nanoparticles as photosensitizers in PDT. They constructed a
UiO-type MOF, DBO-UiO, from 5,15-di(p-benzoato) porphyrin (H2DBP) cores and Hf-oxo
clusters. The nanoparticles of DPB-UiO were able to generate twice the 1O2 as the ligand alone
under the same conditions. To test the performance of DBP-UiO as a PDT therapeutic, they
conducted in vitro experiments on the human head and neck cancer cells SQ20B and showed
that cells treated with DBP-UiO had lower viability under light irradiation. To further enhance the

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Trends in Chemistry

Trends in Chemistry

Figure 4. Metal–Organic Frameworks (MOFs) Are Therapeutic Agents. (A) Common mechanisms of reactive oxygen
species generation through the excitation of a photosensitizer. (B) Common porphyrin-based ligands used in photodynamic therapy
(PDT)-active MOFs. (C) Cervical cancer cell (HeLa) viability on treatment with PCN-224 under different conditions [52]. The toxicity of
PCN-224 increased significantly when the TCPP ligand was excited by the light. (D) Folate-modified PCN-224 has higher
penetration ability towards a folic acid acceptor-rich cell line [52]. (E) In vivo tumor growth on treatment with Hf PDT MOFs under
X-ray dosage [56]. The black arrow represents MOF nanoparticle treatment and the red arrows denote multiple X-ray dosing.
(F) Design and synthetic demonstration of multifunctional PDT system [65]. Adapted, with permission, from [52,56,65].

PDT efficacy, Lin and coworkers [51] replaced the porphyrin core with a chlorin core and con-
structed a similar MOF, DBC-UiO [DBC = 5,15-di(p-benzoate) chlorin]. DBC-UiO has a redshifted
absorption spectrum and an 11-fold increase in extinction coefficient, resulting in a PDT efficiency
three times that of DPC-UiO.

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Trends in Chemistry

To better target tumor cells, Park and coworkers modified the MOF PCN-224 with folic acid (FA)
to increase the affinity of PCN-224 for tumor cells [52]. Some tumor cells, such as cervical tumor
cells, are known to overexpress FA receptors on their cellular membranes. Through the installa-
tion of FA on the Zr-oxo clusters, PCN-224 gains a higher affinity for ovarian cancer cells, indi-
cated by the lower viability of ovarian cancer cells compared with the FA receptor-negative
cell line A549 on treatment with FA-PCN-224 (Figure 4C,D). Beside FA, more tumor-targeting
molecules have also been utilized to increase the affinity of MOF nanoparticles for tumor cells
[48,53–55].

Limited by the penetration depth of visible light, PDT is mostly utilized to treat superficial tumors
such as skin lesions and esophageal cancer. Unlike visible light, X-rays can penetrate soft tissue
and potentially excite X-ray sensitizers to generate ROS. Lan and coworkers constructed 2D
MOFs (Hf-BPY-Ir and Hf-BPY-Ru) with [Hf6O4(OH)4(HCO2)6] clusters and [Ir(bpy)(ppy)2]+- or
[Ru(bpy)3]2+-derived tricarboxylate ligands [56]. The Hf clusters in the 2D MOFs can effectively
absorb X-rays and transfer the energy to the [Ir(bpy)(ppy)2]+ or [Ru(bpy)3]2+ moiety in the organic
linker, subsequently generating 1O2 from 3O2. This energy-transfer pathway was verified by
radioluminescence, where the luminescence from the Ru/Ir moiety could be excited by X-rays.
Importantly, the 2-Gy X-ray dose is low compared with the 20–40-Gy doses used in radiotherapy.
Moreover, the synthesized MOFs have nanosheet morphologies with thicknesses of about 1.2 nm,
believed to be optimal for rapid ROS diffusion within the pores. In vitro experiments were
conducted with CT26 (murine colorectal carcinoma) and MC38 (murine colon adenocarcinoma)
cell lines to confirm the anticancer efficacy. These conclusions were further confirmed by in vivo
experiments, whereby 1 week of the injection and X-ray treatment inhibited and reversed tumor
growth (Figure 4E). These results have shown that an X-ray PDT strategy can treat deeply seated
tumors with a low X-ray dosage, broadening the applicability of PDT. The same research group has
furthered the development of this strategy by providing more examples of X-ray PDT with different
MOFs and singlet-O2 generation moieties [57–59].

Combined Techniques
Owing to their porous nature, MOFs offer the potential of bioactive molecule encapsulation to
further enhance therapeutic activity. In pursuit of this advance, researchers have been creative
in combining PDT-active MOFs with other therapeutic reagents to realize more advanced syner-
gistic therapy. For example, Lin and coworkers [60] successfully combined immunotherapy and
X-ray PDT using MOF nanoparticles. They designed an X-ray PDT-active MOF with an encapsu-
lated immunoregulatory enzyme inhibitor. The embedded inhibitor can trigger systemic immunity
to prevent regrowth of the tumor cell after the termination of X-ray PDT. In another example, Yang
and coworkers combined photothermal therapy (PTT) with PDT by using a ferriporphyrin (FeP)
MOF to encapsulate heat shock protein 70 small interfering RNA (Hsp70 siRNA) [61]. The
decreased thermal tolerance endowed by Hsp70 siRNA in synergy with the ROS generation on
near-IR (NIR) laser excitation of the FeP core results in effective damage to the tumor. More exam-
ples of combined therapy with PTT and PDT have been widely reported in various MOF platforms,
indicative of the versatility of the MOFs in combined PTT/PDT therapy [62–64]. Beside combined
therapy with PTT and PDT, a more complicated multicomponent system is represented by a
recent example from Li and coworkers (Figure 4E) [65]. Tumor cells can produce GSH to reduce
damaging ROS. Furthermore, the long-term efficacy of PDT can be reduced by the production of
protumor factors after massive cell death, particularly angiogenic factors. Therefore, Zhang and
coworkers furthered the PDT application of PCN-224 by equipping the MOF with a MnO2 shell
to oxidize GSH, after which apatinib, an antiangiogenic reagent guest molecule, can be released.
This sophisticated system has proved highly efficient in reducing the size of several tumors in
in vivo experiments.

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Trends in Chemistry

Concluding Remarks Outstanding Questions

In summary, we have highlighted some recent unique examples of MOFs in biomedical applica- Metal–organic frameworks (MOFs) of
tions. Although MOFs are promising candidate materials for biomedical applications given their particle sizes between 30 and 300 nm
are most successful for introduction
tunable porosity and versatile chemical functionality, most reports to date have been exploratory
into living cells. What can be done to
and research in this domain remains in its infancy. As biologically applicable MOFs come of age, it further reduce the diameter of MOFs
is necessary to continually identify instances where MOFs offer augmented or auxiliary function- whose sizes currently cannot be re-
ality and understand the origin of these features through the execution of systematic studies duced to the nanometer scale and
what is the physical limit to this size
and theoretical modeling of structure–property relationships. The adjoined expansion of MOF
reduction?
modifications, the neutralization of synthetic and processing limitations, and more proof-of-
concept biological studies of MOF and MOF-composite materials will naturally lead to answers Typical MOFs studied for biological
for current obstacles (see Outstanding Questions). applicability exhibit low cytotoxicity.
However, many MOFs, particularly
ultrastable MOFs, contain heavy
Acknowledgments
metals, which threaten cytotoxicity
The authors thank the Center for Gas Separations, an Energy Frontier Research Center funded by the US Department of
issues after metabolism. How can the
Energy, Office of Science, Basic Energy Sciences under award number DE-SC0001015, the Robert A. Welch Foundation long-term biodistribution of these de-
through a Welch Endowed Chair to H-C.Z. (A-0030), and the Qatar National Research Fund under award number graded MOF components be studied
NPRP9-377-1-080. The authors also acknowledge the financial support of the US Department of Energy Office of Fossil and pinpointed in living organisms
Energy, the National Energy Technology Laboratory (DE-FE0026472), and National Science Foundation Small Business and what could this divulge regarding
Innovation Research (NSF-SBIR) under grant no. 1632486. C.T.L also thanks the National Science Foundation Graduate safer, biological use of heavy-metal
Research Fellowship under grant no. DGE: 1252521. MOFs?

How can MOF structures be designed

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